The method of producing chlorinol containing o-hydroxyphenyl group

 

(57) Abstract:

Usage: in the medical industry. The inventive method of producing chlorinol containing 0-hydroxyphenyl group f-crystals 1,2,3, where 1A 4-C1, 2-0 HOC6H4, R006 - CH3; 16 4-C1, 2-0 - HOC6H4, R006 - CF3; 1V 4-C1, 2-0 HOC6H4, R006 - C6H5; 1G 4-C1, 2-0 HOC6H4, R005-CN; 1D 4-C1, 2 - HOC6H4, R005 - COOC2H51E 4-C1, 2-0 HOC6H4, R005 C6H5; 1G 4-C1, 2 - o-HOC6H4R==H; 1Z 4-C1, 6-0 HOC6H4R=H; 1i 4-C1, 2-0 HOC6H4R=H; 1K 4-C1, 4-0 HOC6H4R=6 C6H5; 2A R=H 2B R=4 OC3H7; 2B, R=5-Br; 2G R=5 NO2; 2D R=3,5-C1; 3A R=h: Reagent 1: (0-hydroxyphenyl)dihydrothieno. The reagent 2 - chloranhydride organic or inorganic acid (phosphorus oxychloride, phosphorus trichloride, chloride thionyl, cyanuric chloride, Piatigorsky phosphorus). The process is conducted in a medium of dimethylformamide at a molar ratio of reactants is 1: 2. The structure of the formula 0-hydroxyproline groups 1, 2 and 3. 1 C.p. f-crystals.

The invention relates to an improved method of producing chlorinol containing o-hydroxyphenyl group, of General formula I-III I

< / BR>
where Ia 4-CL; 2-o-HOC6H6; R = 6-
Iك 4-Cl; 2-o-HOC6H4; R = 5-CN

Ia 4-Cl; 2-o-HOC6H4; R = 5-COOC2H5< / BR>
Ie 4-Cl; 2-o-HOC6H4; R = 5-C6H5< / BR>
If 4-Cl; 2-o-HOC6H4; R = H

Z 4-Cl; 6-o-HOC6H4; R = H

AI 2-Cl; 4-o-HOC6H4; R = H

IC 2-Cl; 4-o-HOC6H4; R = 6-C6H5< / BR>
IIa R = H

IIb R = 4' -OC3H7< / BR>
IIb R = 5' -Br

G R = 5' -NO2< / BR>
D R = 3' , 5' -Cl2< / BR>
IIIa R = H is used as intermediate products in the synthesis of universal stabilizers for polyethylene, i.e., has both thermal and sitosterolaemia efficiency, to obtain hydrazinopyridazine when the matrix synthesis of reactive test papers for rapid semi-quantitative determination of trace metals [1], and obtain the initial products in the synthesis blockers and vasodilator substances on the basis of the compounds III [2].

A method of obtaining 3-chloro-6-(2,4-dioksifenil)pyridazine (YI), which consists in the condensation of 3,6-dichloropyridazine (IY) c resorcinol (Y) in the conditions of the reaction, Friedel -, I. e. condensation in the environment of dry nitrobenzene with gradual addition of anhydrous aluminum chloride as catalyst when the temperature is th mass with a mixture of ice-water-hydrochloric acid, Department nitrobenzene layer from water, distillation of nitrobenzene with water vapor and the selection of the target product from the residue [3].

Circuit 1

< / BR>
The disadvantages of this method are used as high-boiling solvent toxic nitrobenzene, which requires compliance with specific measures for safety, the complexity of the allocation process of the target product. Moreover, this method of obtaining the target compounds are limited to the use in the reaction only of resorcinol, as the interaction of 3,6-dichloropyridazine (IY) with hydroquinone (YII) stops at the stage of receiving the broadcast YIII, and catechol, phenol, 3 - and 4-chlorophenols and anisole practically do not react with IY [3].

Dichloropyrimidine also interact with resorcinol (Y) in the conditions of the reaction, Friedel -, however, the reaction takes place selectivity compared with 3,6-dichloropyridazine (IY), i.e., both chlorine atoms react arilirovaniya as shown in example 2-methyl-4,6-dichloropyrimidine (IX) in scheme [4].

Scheme 2

< / BR>
A method of obtaining 3-chloro-6-(2-hydroxyphenyl)pyridazine (IIIa) (prototype for the synthesis of compounds IIIa) and its substituted IIIB, based on the corresponding 6-(2-hydroxyphenyl)-3(2H)-pyridazinones for their consistent implementation in a single reaction vessel [5]. stage 1 - the protection of the phenolic group in the compounds of Ha-in heating in an excess of acetic anhydride at 100aboutC for 1 h 45 min, evaporation of the mixture under reduced pressure, the remaining processing of the reaction mixture with methanol, water and the emission of compounds Chi-century

Scheme 3

< / BR>
where (a) R = H b) R = 4-F,) R = 5-Br, 2-stage treatment with phosphorus oxychloride compounds Pendant-in at 55-60aboutC for 40 min, the subsequent distillation of the excess of phosphorus oxychloride under reduced pressure, the decomposition of the reaction mixture with ice water, keeping the resulting slurry during the night at the 5aboutAnd isolation of intermediates XIIa-in

Scheme 4

< / BR>
where (a) R = H b) R = 4-F,) R = 5-Br

3rd stage - the removal of the protective groups with phenolic hydroxyl by treatment of compounds Ha-2 N. aqueous solution of sodium hydroxide in the presence of ethanol by stirring at room temperature for 1 h, dilute the reaction mixture with water, acidification with concentrated hydrochloric acid and the selection in the usual way target compounds IIIa-century, the Total yield of compound IIIa is 78%.

Scheme 5

< / BR>
where (a) R = H b) R = 4-F,) R = 5-Br

However, this method has several disadvantages due to megastudy assignee of phosphorus oxychloride and acetic anhydride as both reagent and solvent necessitates distillation under vacuum of the excess and the subsequent disposal of wastewater phosphorus oxychloride and acetic anhydride.

The closest to this invention to the technical essence and the achieved result is the method of synthesis of chloropyrimidine containing o-hydroxyphenyl group, by chlorination of the corresponding (o-hydroxyphenyl)dihydropyrimidines (XIII) in the chloride environment taanila (SOCl2with the addition of dimethylformamide (DMF) (10: 1 v/v) at a temperature of 85-90aboutC for 1 h 40 min, followed by distillation of excess chloride tiomila under reduced pressure, the remaining processing of the reaction mixture with ice water and the selection of target products by the known methods [6].

Scheme 6

R R

The disadvantages of this method of obtaining chlorinol containing o-hydroxyphenyl group, is the use of aggressive chloride tiomila both as reagent and solvent, and the associated need vacuum distillation of excess and waste chloride tiomila.

The aim of the invention is to simplify and expand the range gloriously substances.

This goal is achieved by a method of producing chlorinol containing o-hydroxyphenyl group, by reacting equimolar amounts with teleformula followed by separation of the product by known methods.

In the present method equimolar amount of (o-hydroxyphenyl)-dihydrothieno (XIIIa-K, Hua-d, Ha) and acid chlorides SOCl2, POCl3etc., is dissolved in dimethylformamide and the reaction mass stirred at room temperature (see experiments 1, 4-8, 11-15), and for some compounds require heating at 80-85aboutC for 1.5 hours (see experiments 2, 9, 10, 16). Then the target product are pouring the reaction mixture into water and separating the precipitate as dimethylformamide in an inert solvent and miscible with water in all respects.

Scheme 7

R__________ R

the continuation of the scheme 7

_______< / BR>
< / BR>
The structure of the target compounds Ia, IIa-d, IIIa and their precursors, respectively XIIIa-XIYa-d, Ha is the presence in the molecule of phenolic fragment, a hydroxyl group which reacts with acid chlorides of the acids. For example, phenols interact with chloride tiomila, phosphorus trichloride or phosphorus oxychloride with the formation of stable arolovich esters XY-XVII.

(PhO)3P (PhO)2SO

Therefore, when the synthesis of compounds IIIa-b (scheme 3-5, prototype) to prevent phosphorylation of phenolic hydroxyl and selective stage ( 3).

Chloride thionyl less effective than phosphorus oxychloride and when interacting with dihydrojasmonate are not formed chlorine, and -(chlorosulfonyl)asinone XVIII, XIX [7]:

< / BR>
It is known that phosphorus oxychloride, chloride tional and other anhydrides interact with dimethylformamide (DMF) with the formation of iminium salts DMF-l3(XX), DMF-SOCl2(XXI) and so on, who have a more strong electrophilic properties compared to the original l3and SOCl2[ ].

(CH3)CHCl C (CH3)O (CH3) = ClPO2C

Iminium salts XX, XXI, generated in situ, react with phenols and substituted in several directions: - interact with the hydroxyl group in the anhydrous solvent to form salts XXII, subsequent hydrolysis of which leads to the labile allformats XXIII [8].

C6H5OH + DMF POCH3) = CHOCC

- formuliruut benzene ring substituted phenols

+XX(XXI)____< / BR>
- replace the hydroxyl group in the activated phenols with chlorine atom [9]

+XXI____< / BR>
where X = NO2CH(CH3)2< / BR>
In addition, heterocyclic hydroxyl group may be substituted chloroethanol feature of the developed method compared to the prototype is the use of an excess of dimethylformamide as solvent instead of chloride tiomila and phosphorus oxychloride. This provides a significant practical advantage of the proposed method for reduction of the yield of target products to use aggressive gloriouse substances only required for the reaction quantities when interacting with polyfunctional original substances containing both phenolic and heterocyclic hydroxyl group (XIIIa-XIYa-d, Ha).

The method is illustrated by the following examples.

P R I m e R 1. Getting 4-chloro-2-(2' -hydroxyphenyl)-6-methylpyrimidine (Ia).

a) To 360 ml of dry baltimoremd while cooling and stirring, was added dropwise 90 ml (0.95 mol) of phosphorus oxychloride, in the solution contribute 96 g (0.475 mol) of 4-hydroxy-2-(2' -hydroxyphenyl)-6-methylpyrimidine and stirred at room temperature for 1.5 hours Then the reaction was poured into water, the resulting precipitate is filtered off, washed with water until neutral and dried. Get 100 g (97%) of 4-chloro-2-(2-hydroxyphenyl)-6-methylpyrimidine (Ia), so pl. 134-135,5aboutC (from ethanol). In the presence of the starting spots in the received connection (Silufol UV-254, eluent methylene chloride or benzene), the solution is filtered through a layer of silica gel.

Found, %: C 59,73; H 3,84; N 12,70; Cl 16,19.

C11Nlee scale, M. D.): 12,70 (1H, s, OH), 8,40 (1H, D. D. J - 1.5 and 8 Hz, 6' -H), 7,38 (1H, m, 4' -H), 7,05 (1H, s, 5-H), OF 6.96 (2H, m, 3' -H and 5' -H), 2,54 M. D. (3H, s, CH3).

b) in the conditions of example 1A of 96 g (0.475 mol) of 4-hydroxy-2-(2' -hydroxyphenyl)-6-methylpyrimidine, 71 ml (0.95 mol) of chloride tiomila in 360 ml of dry dimethylformamide receive Ia with the release of 98%. so pl. and IR spectrum which correspond to the sample of example 1A.

in) 3.7 g (0.02 mol) of cyanuric chloride added portions in 15 ml of dry dimethylformamide under cooling, then add 2 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-6-methylpyrimidine and stirred at room temperature for 3 h Then the reaction was poured into water, the precipitate was separated, washed with water, dried, and purified on a column of silica gel with elution methylene chloride and receive with the release of 50% of the target compound Ia, so square and the IR spectrum which correspond to the sample of examples 1A, b.

P R I m m e R 2. Getting 4-chloro-2-(2'-hydroxyphenyl)-6-trifloromethyl - rimidine (IB).

1.5 ml (0.02 mol) of chloride tiomila added dropwise while cooling and stirring to 20 ml of dry dimethylformamide, and after 15 min the solution make of 2.56 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-6-cryptomaterial and the reaction mixture is heated at a temperature hidroxiaril)-6-cryptomaterial with the release of 95%, so pl. 130,5-131, 5mmaboutC.

Found, %: From 48.4; H 2,32; CL 13,2; F 21,3; N 10,1.

C11H6ClF3N2O .

Calculated, %: C 48,1; H 2,18; Cl 12,9; F 20,8; N 10,2.

Range PMR (dCl3): 11,57 (1H, s, OH), 8,44 (1H, D. d, J = 1.5 and J = 8 Hz, 6' -H), TO 7.50 (1H, s, 5-H), WAS 7.45 (1H, m, 4' -H), 7,01 (2H, m, 3' -H and 5' -H).

P R I m e R 3. Getting 4-chloro-2-(2' -hydroxyphenyl)-6-phenylpyrimidine (Ie).

a) In the conditions of example Ia of 2,82 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-6-phenylpyrimidine and 2 ml (0.02 mol) of phosphorus oxychloride in 20 ml of dry dimethylformamide get In with the release of 25%, so pl. 101-102aboutC.

Found, %: C 67,93; N 4,12; N 9,41, Cl 12,74.

WITH16H11lN2O.

Calculated, %: C 67,96; H To 3.89; N To 9.91; Cl 12,57.

b) In the conditions of example 2 from 2,82 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-6-phenylpyrimidine and 1.5 ml (0.02 mol) of chloride tiomila in 20 ml of dry dimethylformamide get 4-chloro-2-(2' -hydroxyphenyl)-6-phenylpyrimidine with the release of 93%, so square and the IR spectrum which correspond to the sample of example 3A.

P R I m e R 4. Getting 4-chloro-2-(2' -hydroxyphenyl)-5-cyanopyrimidine (Iك).

In the conditions of example 1A from 2,13 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-5-cyanopyrimidine and 2 ml (0.02 mol) of phosphorus oxychloride in 1 is 57,02; N 2,52; N 17,79; Cl 14,67.

C11H6ClN3O.

Calculated, %: 57,03; N 2,61; N 18,14; CL 15,31.

Range PMR (dCl3): 11,90 (1H, s, OH), 8,86 (1H, s, 6-H), TO 8.41 (1H, d , J = 1.5 and J = 8 Hz, 6' -H), 7,49 (1H, m, 4' -H), 7,05-OF 6.96 (2H, m, 3' -H and 5' -H).

P R I m e R 5. Getting 4-chloro-2-(2' -hydroxyphenyl)-5-carbamaxepine (Ia).

In the conditions of example 1 and from 2,60 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-5-carbamaxepine and 2 ml (0.02 mol) of phosphorus oxychloride in 20 ml of dry dimethylformamide get the target connection with the release of 90%, so pl. 107-109aboutC.

Found, %: C 55,96; N. Of 3.96; N 10-03; Cl 12,87.

C13H11ClN2O3.

Calculated, %: C 56,02; H 3,98; N Of 10.05; Cl 12,72.

Range PMR (dCl3): 12,37 (1H, s, OH), 9,13 (1H, s, 6-H), 8,44 (1H, D. d, J = 1.55 and J = =8 Hz, 6' -H), WAS 7.45 (1H, m, 4' -H), 7,00 (2H, m, 3' -H and 5' -H), OF 4.45 (2H, q, J = 7 Hz, CH2), to 1.42 (3H, t, J = 7 Hz, CH3).

P R I m e R 6. Getting 4-chloro-2-(2' -hydroxyphenyl)-5-phenylpyrimidine (Ie).

In the conditions of example 1 and of 2,82 g (0.01 mol) 4-hydroxy-2-(2' -hydroxyphenyl)-5-phenylpyrimidine and 2 ml (0.02 mol) of phosphorus oxychloride in 20 ml of dry dimethylformamide get the target connection with the release of 98%, so pl. 133-135aboutC.

Found, %: C 68,0; N. Of 4.05; N 9,94; CL 12,7.

SUB>): 12,51 (1H, s, OH), AT 8.60 (1H, s, 6-H), 8,46 (1H, D. d, J = 1.5 and J = 8 Hz, 6' -H), TO 7.50 (5H, s, s6H5), 7,41 (1H, m, 4' -H), 7,01 (2H, m, 3' -H and 5' -H).

P R I m e R 7. Getting 4-chloro-2-(2' -hydroxyphenyl)pyrimidine (If).

a) 20 ml (0.2 mol) of phosphorus oxychloride was added dropwise while cooling to 100 ml of dry dimethylformamide, and then make an 18.8 g (0.1 mol) 4-hydroxy-2-(2' -hydroxyphenyl)pyrimidine and continue stirring the reaction mixture for 3 hours Further isolation and purification of the product is similar to example 1A. Get 4-chloro-2-(2' -hydroxyphenyl)pyrimidine with an almost quantitative yield, so pl. 100-102aboutC.

Found, %: C Of 57.8; H 3,51; 13,5 N; Cl 17,2.

WITH10H7ClN2O.

Calculated, %: C 58,1; N 3,39; 13,5 N; Cl 17,2.

Range PMR (DMSO): 12,65 (1H, s, OH), 8,87 (1H, d, J = 5.5 Hz, 6-H), 7,66 (1H, d, 5-H), 8,46-TO 6.80 (4H, m, Hphenyl).

b) 15 ml (0.2 mol) of chloride tiomila added dropwise while cooling and stirring to 75 ml of dry dimethylformamide, after 15 min in the solution contribute to 18.8 g (0.1 mol) 4-hydroxy-2-(2' -hydroxyphenyl)pyrimidine and continue stirring the reaction mixture for 3 hours. Further isolation and purification of the product as in example 1A. Get the target product almost quantitative yield, so square And the Nile)pyrimidine (Z).

In the conditions of example 7a from an 18.8 g (0.1 mol) 4-hydroxy-6-(2' -hydroxyphenyl)pyrimidine and 20 ml (0.2 mol) of phosphorus oxychloride in 100 ml of dry dimethylformamide get almost quantitative yield of the target compound Z, so pl. 152-153aboutC.

Found, %: C To 57.9; H Of 3.45; N 13,4; Cl 17,4.

C10H7ClN2O.

Calculated, %: C To 58.1; H 3,39; 13,5 N; Cl 17,2.

Range PMR (DMSO): 12,01 (1H, s, OH), 9,05 (1H, s, 2H), 8,35 (1H, s, 5-H), 8,25-OF 6.78 (4H, m, Hphenyl).

P R I m e R 9. Getting 2-chloro-4-(2' -hydroxyphenyl)pyrimidine (AI).

In the conditions of example 2 of 1.88 g (0.01 mol) of 2-hydroxy-4-(2' -hydroxyphenyl)pyrimidine and 1.5 ml (0.02 mol) of chloride tiomila in 20 ml of dry dimethylformamide get almost quantitative yield of 2-chloro-4-(2' -hydroxyphenyl)pyrimidine, t,pl. 147-148aboutC.

Found, %: C And 57.6; H To 3.33; N 13,6; Cl 17,4.

C10H7ClN2O.

Calculated, %: C To 58.1; H 3,39; 13,5 N; Cl 17,2.

Range PMR (DMSO): 11,83 (1H, s, OH), 8,81 (1H, d, J = 5.5 Hz, 6-H), TO 8.25 (1H, d, 5-H), 8,18-6,85 M. D. (4H, m, Hphenyl).

P R I m e R 10. Getting 2-chloro-4-(2' -hydroxyphenyl)-6-phenylpyrimidine (VBE).

In the conditions of example 2 of 14.1 g (0.05 mol) of 2-hydroxy-4-(2' -hydroxyphenyl)-6-phenylpyrimidine and 7.5 ml (0.1 mol) of chlorine ti is Found, %: C 68,3; H 3,94; N 9,96; Cl 12,6.

C16H11ClN2O.

Calculated, %: C 68,0; H 3,92; 12,5 Cl.

Range PMR (DMSO): 11,33 (1H, s, OH), 8,64 (1H, s, 5-H), 8,44-of 6.73 M. D. (N, m, Nphenyl).

P R I m e R 11. Getting 4-chloro-2-(2' -hydroxyphenyl)hintline (IIA).

a) 4 ml (0.04 mol) of phosphorus oxychloride was added dropwise while cooling to 25 ml of dry dimethylformamide. Then to the solution was added 4.8 g (0.02 mol) 4-hydroxy-2-(2' -hydroxyphenyl)hintline and continue stirring the reaction mixture for 3 hours Further isolation and purification of the product is similar to example 1A. Get almost quantitative yield of 4-chloro-2-(2-hydroxyphenyl)hinzelin, so pl. 160-161,5aboutC, lit. so pl. 157-158aboutC.

Range PMR (DMSO-d6): 13,22 (1H, s, OH), 8,42 (1H, D. d, J = 2 and J = 8 Hz, 6' -H), 8,31 (1H, d, J = 8 Hz, 5-H), 8,19 (2H, m, 7-H and 8-H), 7,86 (1H, m, 6-H), OF 7.48 (1H, m, 4' -H), 7.03 is M. D. (2H, m, 3'H - and 5' -H),

b) 8,32 g (0.04 mol) petaluridae phosphorus added in small portions while cooling to 25 ml of dry dimethylformamide. Then to the solution was added 4.8 g (0.02 mol) 4-hydroxy-2-(2' -hydroxyphenyl)hintline and stirred at room temperature for 3 hours Further isolation and purification of the product is similar to example 1A. Get off exit 95% target sois 3 ml (0.04 mol) of chloride tiomila and 4.8 g (0.02 mol) 4-hydroxy-2-(2' -hydroxyphenyl)hintline in 25 ml of dry dimethylformamide get almost quantitative yield of 4-chloro-2-(2' -hydroxyphenyl)hinzelin, so pl. and IR spectrum which correspond to the sample from example 11a.

g) 3.5 ml (0.04 mol) of phosphorus trichloride was added dropwise while cooling and stirring to 25 ml of dry dimethylformamide. Then to the solution was added 4.8 g (0.02 mol) 4-hydroxy-2-(2' -hydroxyphenyl)hintline and heated at 50aboutWith over 2 hours of Further isolation and purification of the product is similar to example 1A. Get out 98% of the target connection, so square and the IR spectrum which correspond to the sample from example 11a.

P R I m e R 12. Getting 4-chloro-2-(2' -hydroxy-4' -n-propoxyphenyl)hintline (IIB).

In the conditions of example 11a out of 5.92 g (0.02 mol) 4-hydroxy-2-(2' -hydroxy-4' -n-propoxyphenyl)hintline and 4 ml (0.04 mol) of phosphorus oxychloride in 25 ml of dry dimethylformamide get the target connection with the release of 87%, so pl. 115-117aboutC.

Found, %: C 64,56; H A 4.83; N 8,97.

C17H15ClNO2.

Calculated, %: C 64,86; H Of 4.77; N 8,90.

Range PMR (dCl3): 13,52 (1H, s, OH), 8,40 (1H, d, J = 9.5 Hz, 6' -H), TO 8.14 (1H, d, J = =8,5 Hz, 5-H), A 7.85 (2H, m, 7-H and 8-H), 7,54 (1H, m, 6-H), 6,51 (1H, d, J = 2.5 and J = 9 Hz, 5' -H), OF 6.49 (1H, d, J = 2,5 Hz, 3' -H), OF 3.95 (2H, t, och2) and 1.83 (2H, m, CH2), was 1.04 (3H, t, CH3).

P R I m e p 13. Getting 4-chloro-2-(2' -hydroxy-5' -bromfeild and 4 ml (0.04 mol) of phosphorus oxychloride in 35 ml of dry dimethylformamide get with exit 94% 4-chloro-2-(2' -hydroxy-5' -bromophenyl)hinzelin, so pl. 220-222aboutC. According to the mass%of range high resolution (device MAT-8200 firm "Finnigan" M+333,9508. WITH14H8lBrN2O. Calculated: M 333,9509.

Range PMR (dCl3): 13,32 (1H, s, OH), 8,66 (1H, d, J = 2,5 Hz, 6 '-H), OF 8.27 (1H, d, J = 9 Hz, 5-H), OF 7.97 (2H, m, 7-H and 8-H), OF 7.70 (1H, m, 6-H), 7,47 (1H, D. d, J = 2.5 and J = 9 Hz, 4' -H) 6,94 (1H, DD, J = 9 Hz, 3' -H).

P R I m e R 14. Getting 4-chloro-2-(2' -hydroxy-5' -nitrophenylhydrazone (G).

In the conditions of example 11a from 5,66 g (0.02 mol) 4-hydroxy-2-(2' -hydroxy-5' -nitrophenyl)hintline and 4 ml (0.04 mol) of phosphorus oxychloride in 25 ml of dry dimethylformamide get with the release of 50% of the target connection, so pl. 243-245aboutC.

Found, %: C 55,94; H To 2.65; N 13,62.

C14H8ClN3O3.

Calculated, %: C 55,63; N To 2.65; N 13,91.

Range PMR (dCl3): 14,30 (1H, s, OH), 9,52 (1H, d, J = 3 Hz, 6' -H), WITH 8.33 (1H, m, 5-H), 8,30 (1H, D. d, J = 3 and J = 9 Hz, 4' -H), OF 8.04 (2H, m, 7-H and 8-H), TO 7.77 (1H, m, 6-H), 7,13 (1H, d, J' = 9 Hz, 3' -H).

P R I m e R 15. Getting 4-chloro-2-(2' -hydroxy-3' ,5' -dichlorophenyl)hintline (D).

In the conditions of example 11a from 6,14 g (0.02 mol) 4-hydroxy-2-(2' -hydroxy -3' , 5' -dichlorophenyl)hintline and 4 ml (0.04 mol) of phosphorus oxychloride in 25 ml of dry dimethylformamide get out 91% of the target connection, so pl./SUB>N2O. Calculated: M 323,9624.

Range PMR (dCl3): 14.24 from (1H, s, OH), 8,49 (1H, d, J = 2,5 Hz, 6' -H), 8,31 (1H, d, J = =8,5 Hz, 5-H), 8,00 (2H, m, 7-H and 8-H), TO 7.75 (1H, m, 6-H), TO 7.50 (1H, d, J = 2.5 Hz, 4' -H).

P R I m e R 16. Obtain 3-chloro-6-(2' -hydroxyphenyl)pyridazine (IIIA).

In the conditions of example 2 of 1.88 g (0.01 mol) of 3-hydroxy-6-(2' -hydroxyphenyl)pyridazine and 1.5 mol (0.02 mol) of chloride tiomila in 20 ml of dry dimethylformamide get with exit 87% 3-chloro-6-(2' -hydroxyphenyl)pyridazine, so pl. 186-188aboutC, lit. so pl. 187,5-188,5aboutC.

Thus, the proposed method allows you to:

to address the shortcomings of the prototype, namely, the use of acetic anhydride, chloride tiomila and phosphorus oxychloride as solvents, evaporation of the reaction mixture under reduced pressure and the disposal of waste anhydrides;

to expand the range gloriously substances to obtain the target compounds, i.e. successfully used as the liquid (phosphorus oxychloride, phosphorus trichloride, chloride thionyl) and crystalline (cyanuric chloride, Piatigorsky phosphorus) anhydrides of organic and inorganic acids in equimolar amounts relative to the (o-hydroxyphenyl)dihydrothieno;

to carry out the synthesis of mn is in (IIIa) in one technological stage (scheme 7) instead of the three-stage, described in patents [7-9] (see scheme 7 schematic 3-5).

1. The METHOD of producing CHLORINOL CONTAINING O-HYDROXYPHENYL GROUP of the General formula I

< / BR>
where R1- N.;

or

< / BR>
where Cl is in the 2nd position R11- N, 6-C6H5, oxyphenylic ring attached at the 4-th position of Cl - in the fourth position, R11- N, 5(6)-C6H5, 6-CH3A 6-CF3, 5-CN, 5-SOOS2H5, oxyphenylic ring attached on the 2nd position with R' - H, 41-(OC3H7), 51-Br, 51-NO2, 31, 51-Cl2,

< / BR>
by reacting the corresponding (o-hydroxyphenyl)dihydrothieno with acid anhydrides in the presence of a solvent, characterized in that, to simplify the process, the interaction is carried out at a molar ratio of (o-hydroxyphenyl)dihydrothieno with the acid chloride of the acid of 1 : 2 as the solvent used dimethylformamide.

2. The method according to p. 1, characterized in that the carboxylic acid is used SOCl2, POCl3, PCl3, PCl5or cyanuric chloride.

 

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The invention relates to a method for obtaining new pyrimidine derivatives possessing valuable fungicidal properties, which can find application in agriculture

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to derivatives of substituted pyridazinylamine of formula or to their pharmaceutically acceptable salts or hydrates, where X is C or N; Y is O or S; W is C or N; R1, R2, R3 each independently represents hydrogen or halogen; R4, R5, R6 each independently represents hydrogen, halogen, C1-C8-straight or branched alkyl, C1-C8-straight or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7; R7 independently represents hydrogen or C1-C8-straight or branched alkyl. The invention also relates to a method of producing said compounds, to pharmaceutical compositions containing said compounds and to use of the said compounds as picornavirus inhibitors for preventing and/or treating diseases caused by pircornaviruses.

EFFECT: novel compounds have useful biological properties.

10 cl, 1 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula IV: , where: R1 represents Cl or F; R3 represents H, Me, Et, OH, MeO-, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, HOCH2CH2-, , , , , or , R7 represents methyl or ethyl which are optionally substituted with one or more F; R8 represents Br, I or SMe; and R9 represents H, C1-C4alkyl, Cl or CN where said alkyl it optionally substituted with one or more groups independently chosen from F or CN provided when a) R1 represents F, R8 represents Br, R9 represents H, and R7 represents either Me, or Et, then R3 cannot represent HOCH2CH2O; b) R1 represents F, R8 represents I, R9 represents H, and R3 represents MeO then R7 cannot represent Me; c) R1 represents F, R8 represents Me, R9 represents H, and R3 represents HOCH2CH2O then R7 cannot represent Me; and d) R1 represents F, R8 represents Br, R9 represents H, and R3 represents cyclopropyl-CH2O then R7 cannot represent Me, as well as to the use of said compound in preparing a drug for treating hyperproliferative disorder or an inflammatory state and to a pharmaceutical composition which inhibits MEK.

EFFECT: there are prepared and described new compounds effective in treating hyperproliferative diseases, such as cancer and inflammation.

17 cl, 25 ex, 8 tbl, 15 dwg

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula

or a pharmaceutically acceptable salt thereof, where: R1 is O or F; R3 is H, Me, Et, OH, MeO, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, HOCH2CH2-, , , , , or ; R7 is cyclopropyl-CH2- or C1-C4alkyl, where said alkyl is optionally substituted with one or more F; R8 is Br, I or SMe; and R9 is CH3, CH2F, CHF2, CF3, F or Cl. The invention also discloses use of said compound in preparing a medicinal agent for treating a hyperproliferative disorder or an inflammatory condition, as well as a MEK inhibiting pharmaceutical composition.

EFFECT: novel compounds are obtained and described, which are MEK inhibitors and can useful in treating hyperproliferative diseases such as cancer and inflammation in mammals and inflammatory conditions.

13 cl, 25 ex, 8 tbl, 15 dwg

FIELD: organic chemistry, medicine, biochemistry, pharmacy, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to derivatives of aminodicarboxylic acids of the general formula (I) and a medicinal agent able to stimulate activity of soluble guanylate cyclase being independently of the presence of the heme group comprising in it and able to cause relaxation of vessels and comprising at least one compound of the general formula (I). Agent is designated for treatment of cardiovascular diseases and for treatment of the central nervous system diseases characterizing by disorder of the system NO/cGMP, and shows high bioavailability and effectiveness.

EFFECT: improved and valuable medicinal properties of agent.

7 cl, 232 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-hetaryl-substituted derivatives of 1,2-tropolones of the general formula (Ia): wherein R1 and R2 mean (C1-C6)-alkyl; R3 means hydrogen atom, (C1-C6)-alkyl, nitro-group; Het means six-membered nitrogen heterocycle condensed with one or two benzyl rings that can be substituted with substitutes chosen from group comprising halogen atom, nitro-group, (C1-C6)-alkyl, oxy-(C1-C6)-alkyl, secondary amino-group chosen from anilino-, substituted anilino-, hydroxyethylamino-group, or tertiary amino-group chosen from morpholino-, piperidino-, piperazino-group, 1H-1-imidazolyl. Also, invention relates to a method for synthesis of 2-hetaryl-substituted derivatives of 1,3-tropolone. Method involves condensation of benzoquinones-1,2 with 2-methylheterocycles at heating in the presence of acetic acid taken in the amount providing its role as both a catalyst and a solvent. Also, invention relates to a pharmaceutical composition with antibacterial effect based on 2-hetaryl-substituted derivatives of 1,3-tropolone.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 5 tbl, 3 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing optically pure voriconazole via: a) coupling reaction of 1-(2,4-difluorophenyl)-2(1H-1,2,4-triazol-1-yl)ethanone with 4-(1-bromoethyl)-6-(4-chlorophenylsulphanyl)-5-fluoropyrimidine in Reformatsky reaction conditions to obtain the desired (2R,3S)/(2S,3R) enantiomeric pair, b) splitting the thiol fragment from the enantiomer to obtain racemic voriconazole; and c) extracting the desired optically pure voriconazole via optical separation of the enantiomer using an optically active acid.

EFFECT: improved method.

4 cl, 7 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed compound relates to novel biaryl-meta-pyrimidine, corresponding to structure (A) and their pharmaceutically acceptable salts. In structure (A): X is selected from group consisting of bond O, and CH2, and Y represents bond; or X and Y together can represent bond; each R1 and R2 independent on each other are selected from group consisting of H and unsubstituted C1-C6alkyl; each of p, q, r, n, m independent on each other represents integer number 0 or 1; G0 is selected from group consisting from N and CH; each G represents independently CH, N, CR6 or C, when bound with X, on condition that not more than two groups of G represent N, and each R6 does not depend on another R6; R5 represents methyl, Values of other radicals are given in the invention formula.

EFFECT: compounds possess inhibiting activity with respect to family of JAK kinases, in particular JAK2 kinases, and can be used in treatment of myeloproliferative disease, which results from genetic or protein fusions, as a result of increase of function of kinase from family of JAK kinases in cell signal transmission, as well as in treatment of true polycythemia, primary thrombocytopenia, myeloid fibrosis with myeloid metaplasia, proliferative diabetic retinopathy, cancer or eye diseases.

66 cl, 2 tbl, 246 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine carboxylate derivatives having herbicidal activity, as well as agriculturally acceptable derivatives thereof from a carboxylic acid group, which are esters or salts. In formula (I): Q is halogen; R1 is H; W is H; X is halogen; Y is C1-C4alkoxy; Z is halogen.

EFFECT: invention also relates to a herbicidal composition containing said compounds and a method of inhibiting undesirable plants.

4 cl, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (I) X=N or C-R3; R1 stands for proton, saturated or unsaturated linear alkoxy radical, which has 2-5 carbon atoms; cycloalkyloxy radical, which has to 6 carbon atoms, saturated linear alkylmercapto radical, which has 1-3 carbon atoms; amino radical, having 1-10 carbon atoms, selected from saturated or unsaturated linear mono- or dialkylamino radical, or cycloalkylamino radical, cyclic amino radical, and each of cyclic groups can be substituted with 1-2 metal groups, or benzylaminogroup; R2 represents proton, saturated or unsaturated, linear alkyl radical, which has 1-5 carbon atoms, or cyclic aliphatic radical, which has to 6 carbon atoms, trifluoromethyl, stiryl or methylmercaptogroup; R3 stands for trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyanogroup or alkoxycarbonyl sunstituent, which has 1-3 carbon atoms in alkoxygroup.

EFFECT: obtaining novel 2-nitroheterylthiocyanates of general formula (I), or their pharmaceutically acceptable additive salts with acids or bases, probably in crystalline form, possessing activity with respect to strains of fungi, causative agents of fungal infections, their application for treatment of fungal infections, as well as obtaining based on them pharmaceutical composition.

8 cl, 3 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 2-nitroheterylthiocyanates, particularly 4-rhodano-5-nitropyrimidine and 2-rhodano-3-nitripyridine derivatives of general formula (I), optionally in crystalline form or in form of pharmaceutically acceptable addition salts thereof with acids or bases, having activity on fungal strains, fungal infection agents, for producing pharmaceutical compositions that are suitable for local application. The compounds are also active on strains that are resistant to existing drugs. In general formula (I) X=N or C-R3, R1 denotes a proton, a saturated or unsaturated linear alkoxy radical having 1-5 carbon atoms; a cycloalkyloxy radical having up to 6 carbon atoms; a saturated linear alkylmercapto radical having 1-3 carbon atoms; an amino radical having 1-10 carbon atoms, selected from a saturated or unsaturated linear mono- or dialkylamino radical or a cycloalkylamino radical, cyclic amino radical. Each of the cyclic groups can be substituted with 1-2 methyl groups, or a benzylamino group; R2 denotes a proton, a saturated or unsaturated linear alkyl radical having 1-5 carbon atoms, or a cyclic aliphatic radical having up to 6 carbon atoms, trifluoromethyl, styryl or methylmercapto group; R3 denotes a trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyano group or an alkoxycarbonyl substitute having 1-3 carbon atoms in the alkoxy group.

EFFECT: improved properties of compounds.

5 cl, 3 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetology, specifically to an agent for dyeing keratin-containing fibres, first of all, human hairs, containing at least one compound of formula (I) and/or its enamic form, with R meaning allylic group, hydroxyalkyl group with 2-6 carbon atoms, or if required, substituted benzyl group, X- meaning a physiologically acceptable anion, and at least one aldehyde.

EFFECT: invention allows producing dyeing with shine, improved washability and light resistance.

18 cl, 3 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2, known in medicine as Xymedon, involving recrystallisation of hydrochloride, N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 from ethanol and then treated with a sodium hydroxide solution in ethanol. The sodium chloride formed is removed by filtering. Crude N-(β-hydroxyethyl)-4,6-dimethyldihydropyrimidone-2 is separated by evaporating ethanol and purified by double recrystallisation from chemically pure isopropyl alcohol in the presence of aluminium oxide and activated carbon.

EFFECT: method enables to obtain a highly pure product.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to method of producing capecitabine involving the following steps: 1) hydrolysis of a methylacetonide compound to obtain a triol compound of formula , 2) reaction of the triol compound with haloalkyl formate of the given formula in the presence of a mixture of pyridine and triethylamine to obtain a β-anomer rich trialkylcarbonate compound of formula , 3) glycosylation of the trialkylcarbonate compound using 5-fluorocytosine in the presence of an acid, 4) carbamylation of the obtained compound of formula using n-pentylchloroformate, followed by 5) removal of carbonate hydroxy-protective groups of the furan ring.

EFFECT: efficient method of obtaining capecitabine.

7 cl, 4 ex

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